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Publication numberUS4537882 A
Publication typeGrant
Application numberUS 06/609,072
Publication dateAug 27, 1985
Filing dateMay 10, 1984
Priority dateMay 10, 1984
Fee statusPaid
Also published asCA1231942A, CA1231942A1
Publication number06609072, 609072, US 4537882 A, US 4537882A, US-A-4537882, US4537882 A, US4537882A
InventorsDerek Horton, Waldemar Priebe
Original AssigneeOhio State University
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
4-Demethoxy-3'-desamino-2'-halo-anthracycline and pharmaceutical composition containing same
US 4537882 A
Abstract
Compounds of the formula (I), acid addition salts thereof, and pharmaceutical preparations containing the same are disclosed ##STR1## wherein R1 is hydroxy; one of X and X' is hydrogen and the other is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine; one of Y and Y' is hydrogen and the other is selected from the group consisting of hydrogen, hydroxy and --OCOR; one of Z and Z' is hydrogen and the other is hydrogen, hydroxy or --OCOR; and R is a lower alkyl group.
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Claims(12)
What is claimed is:
1. Compounds of the formula (I) ##STR4## wherein R1 is hydroxy; one of X and X' is hydrogen and the other is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine; one of Y and Y' is hydrogen and the other is selected from the group consisting of hydrogen, hydroxy and --OCOR; one of Z and Z' is hydrogen and the other is hydrogen, hydroxy or --OCOR, and R is a lower alkyl group.
2. The compounds of claim 1 wherein X' is iodine or bromine.
3. The compounds of claim 1 wherein X' is iodine.
4. The compounds of claim 2 wherein Z or Z' is hydroxy or --OCOR where R is a lower alkyl group.
5. The compounds of claim 3 wherein Z or Z' is hydroxy or --OCOR where R is a lower alkyl group.
6. The compounds of claim 1 wherein said compound is 4-demethoxy-7-O-(2-iodo-2,6-dideoxy-α-L-manno-hexopyranosyl)adriamycinone.
7. A pharmaceutical preparation useful for treating the growth of implanted tumors comprising a carrier and a therapeutically effective amount of a compound of the formula ##STR5## wherein R1 is hydroxy; one of X and X' is hydrogen and the other is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine; one of Y and Y' is hydrogen and the other is selected from the group consisting of hydrogen, hydroxy and --OCOR; one of Z and Z' is hydrogen and the other is hydrogen, hydroxy or --OCOR, and R is a lower alkyl group; or a pharmaceutically acceptable acid addition salt thereof.
8. The pharmaceutical preparation of claim 7 wherein X' is iodine or bromine.
9. The pharmaceutical preparation of claim 7 wherein X' is iodine.
10. The pharmaceutical preparation of claim 8 wherein Z or Z' is --OCOR or hydroxy where R is a lower alkyl group.
11. The pharmaceutical preparation of claim 9 wherein Z or Z' is --OCOR or hydroxy where R is a lower alkyl group.
12. The pharmaceutical preparation of claim 7 wherein said compound is 4-demethoxy-7-O-(2-iodo-2,6-dideoxy-α-L-manno-hexopyranosyl)adriamycinone.
Description
BACKGROUND OF THE INVENTION

Anthracycline antibiotics including doxorubicin, daunorubicin, and carminomycin have emerged as important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions including acute myloblastic and lymphoblastic leukemias. Doxorubicin (also known as Adriamycin) is the subject of U.S. Pat. No. 3,590,028 and is a prescribed antineoplastic agent used in a number of chemotherapeutic treatments.

The high level of effectiveness and broad spectrum of activity of Adriamycin have lead to numerous efforts to develop anthracycline derivatives which exhibit less toxicity and enhanced activity. Among the derivatives that have been developed and investigated are 4-demethoxyadriamycin, 4-demethoxydaunomycin and certain halogenated derivatives in which the 1- or 2-position in the sugar moiety is substituted by a halogen atom.

2'-Halo derivates of daunomycin, demethoxydaunomycin, doxorubicin and carminomycin are disclosed in U.S. Pat. No. 4,427,664 to Horton et al. U.S. Pat. No. 4,058,519 to Arcamone et al teaches adriamycin derivatives and reactive intermediates, for example, 1-halo-2,3,6-tridoexy-3-fluoroacetamido-4-trifluoroacetoxy-α-L-lyxo or arabino)hexopyranoses. U.S. Pat. No. 4,046,878 to Patelli et al indicates that the reaction proceeds from daunomycin analogs and uses as a sugar the 1-chloro-2,3,6-trideoxy-3-trifluoroacetamido-4-trifluoroacetoxy-α-L-lyxo pyranose.

SUMMARY OF THE INVENTION

The present invention relates to a novel anthracycline antiobiotic which is represented by the formula (I): ##STR2## wherein R' is hydroxy; one of X and X' is hydrogen and the other is a halogen atom selected from the group consisting of fluorine, chlorine, bromine, and iodine; one of Y and Y' is hydrogen and the other is selected from the group consisting of hydrogen, hydroxy and --OCOR; one of Z and Z' is hydrogen and the other is hydrogen, hydroxy or --OCOR wherein R is a lower alkyl group preferably having 1 to 4 carbon atoms.

The present invention also provides pharmaceutical preparations containing the novel compounds of the present invention as active agents. These compositions can be prepared by dispersing or dissolving the compounds or their acid addition salts in any pharmaceutically acceptable non-toxic carrier suitable for the desired mode of administration. Therapeutic compositions of the present invention may be administered parentally by intravenous, intramuscular, intraperitoneal, or other conventional injection. Preferably, the carrier is an aqueous medium buffered to pH 7.2-7.5, the physiological range. Any suitable conventional buffer can be used such as tris phosphates, bicarbonates or citrates. If desired, saline solution can be used.

In a more particular embodiment, the present invention provides compounds of the formula (I) wherein X' is bromine or iodine; and one of Y and Y' and one of Z and Z' is acetoxy or hydroxy.

In a still more particular embodiment, the present invention provides compounds of the formula (I) wherein X' is iodine and Z' is acetoxy or hydroxy.

The compounds of the present invention exhibit a broad spectrum of anti-cancer activity and are effective in the treatment of myelobastic and lymphoblastic leukemia, and melanoma. The compounds can be administered by intravenous or intraperitoneal injection in an aqueous medium buffered to the physiological range.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are derivatives of 4-demethoxydoxorubicin. These compounds are coupled at the 0-7 position of the aglycon with a 2-substituted halo pyranose or furanose ring structure of sugars which are pentose or hexose varieties. Of the halogens, iodine is preferred but bromine, chlorine and fluorine may also be useful. Preferred are α-L-manno or α-L-talo hexopyranose, which sugar isomers particularly sustain or potentiate the biological activity of the coupled compound.

A synthesis suitable for preparing the compounds of the present invention is diagrammed below: ##STR3##

Racemic 4-demethoxydaunomycinone (1) is converted into its 14-bromo derivative by dissolving (1) in chloroform and adding with stirring bromine in chloroform. The general procedure is described by Smith et al, J. Org. Chem., 42 (1977) 3653-3660. The bromo derivative is then readily hydrolyzed by 5% aqueous potassium carbonate in 0.5 hr at 25° C. to afford racemic 4-demethoxyadriamycinone. Alternatively, the bromo derivative may be hydrolyzed by heating to 80° C. in dimethyl sulfoxide water solution for 0.5 to 1 hr. The latter is silylated with tert-butylchlorodimethyl-silane in N,N-dimethylformamide (DMF) in the presence of imidazole to give racemic 14-O-tert-butyldimethylsilyl-4-demethoxyadriamycinone (2). The reaction of L-rhamnal diacetate and N-iodosuccinimide (NIS) with (2) gives a chromatographically separable mixture of (7S,9S)-14-O-tert-butyldimethylsilyl-4-demethoxy-7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-α-L-manno-hexopyranosyl)adriamycinone (3) and its (7R,9R) isomer (4). O-Deacetylation of (3) by conventional saponification with sodium methoxide to give (5), followed by fluoride ion-mediated deprotection at 0-14, furnishes the optically pure, antitumor-active product, (7S,9S)-4-demethoxy-7-O-(2,6-dideoxy-2-iodo-α-L-manno-hexopyranosyl)-adriamycinone (6).

The synthesis of the compounds of the present invention is illustrated in more detail by the following non-limiting examples:

SYNTHESIS EXAMPLE 1 Racemic 14-O-tert-butyldimethylsilyl-4-demethoxyadriamycinone (2)

Racemic 4-demethoxyadriamycinone (891.2 mg, 2.32 mmol), obtained by the process of Smith et al, was dissolved in DMF (12 ml) and imidazole (686 mg, 10.1 mmol) and tert-butylchlorodimethylsilane (559.4 mg, 3.71 mmol) was added. The mixture was stirred for 0.5 hr. at 25° and then poured into dichloromethane. The solution was then washed with water. The organic extract was dried with sodium sulfate and evaporated to give a dark-red oil that was chromatographed on silica gel (100 g) with 20:1 toluene-acetone as eluant. Evaporation of the main fraction gave compound (2), yield 629 mg (54%); m.p. 193°-195°; 1 H-n.m.r. (200 MHz, CDCl3): 13.60, 13.28 (s, 1H, HO-6,11), 8.35, 7.84 (m, 2H, H-1,2,3,4), 5.34 (m, 1H, H-7) 4.86 (AB m, 2H, H-14A,14B), 4.54 (s, 1H, HO-9), 3.54 (bd, 1H, HO-7), 3.26 (dd, 1H J8e,10e 1.8 Hz, H-10e), 3.03 (d, 1H, J10a,10e 18.6 Hz, H-10a), 2.39 (bd, 1H, H-8e), 2.22 (dd, 1H, J7,8a 4.5, J8a,8e 14.8 Hz, H-8a), 0.95 (s, 9H, CMe3), 0.15 (s, 6H, SiMe2).

Anal. Calc. for C26 H30 O8 Si: C, 62.63; H, 6.06. Found: C, 62.37; H, 6.08.

SYNTHESIS EXAMPLE 2 (7S,9S)-14-O-(tert-Butyldimethylsilyl)-4-demethoxy-7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-α-L-manno-hexopyranosyl)adriamycinone (3) and (7R,9R)-14-O-(tert-butyldimethylsilyl)-4-demethoxy-7-O-(3,4-di-O-acetyl-2,6-dideoxy-2-iodo-α-L-manno-hexo-pyranosyl)adriamycinone (4)

i. Compound (2) (629 mg, 1.26 mmol) was dissolved in oxolane (8 ml) and then 3,4-di-O-acetyl-L-rhamnal (417 mg, 1.95 mmol) in acetonitrile (15 ml) was added. The solution was maintained under an atmosphere of dry argon and N-iodosuccinimide (604 mg, 2.68 mmol) was added with stirring. After 3 hrs, further portions of 3,4-di-O-acetyl-L-rhamnal (410 mg, 1.91 mmol) and N-iodosuccinimide (594 mg, 2.64 mmol) were added. The reaction was terminated after a further 3 hrs by pouring the mixture into dichloromethane (150 ml) and sequentially washing the solution with 10% aqueous sodium thiosulfate and water. The organic phase was dried with magnesium sulfate and evaporated.

ii. Column chromatography of the product-mixture on silica gel (100 g) with 50:1 toluene-acetone as eluant and crystallization afforded compound (4) (7R,9R) as the less-polar component; yield 141 mg (27%); m.p. 153°, 1 H-n.m.r. (200 MHz, CDCl3): 13.69, 13.30 (s, 1H, HO-6,11), 8.36, 7.86 (m, 2H, H-1,2,3,4), 5.53 (d, 1H, H-1'), 5.50 (m, 1H, H-7), 5.15 (t, 1H, H-4'), 4.93 (d, 1H, H-14A), 4.84 (d, 1H, H-14B), 4.53 (dd, 1H, J1',2' 1.6, J2',3' 4.3 Hz, H-2'), 4.44 (dd, 1H, J3',4' 8.9 Hz, H-3'), 4.26 (qd, 1H, J4',5' 10.2, J5',6' 6.2 Hz, H-5'), 4.19 (s, 1H, HO-9), 3.31 (bd, 1H, H-10e), 3.15 (d, 1H, J10a,10e 19.4 Hz, H-10a), 2.43 (bd, 1H, J8a,8e 14.9 Hz, H-8e), 2.06, 2.04 (s, 7H, 2×OAc, H-8a), 1.25 (d, 3H, H-6'), 0.96 (s, 9H, CMe3), 0.15, 0.14 (s, 3H, Me2 Si).

Anal. Calc. for C36 H43 IO13 Si: C, 51.55; H, 5.17; I, 15.13. Found: C, 51.39; H, 5.17; I, 15.23.

The more polar diastereomer (3), having the 7S,9S configuration, was isolated in a yield of 155.2 mg (29%). Recrystallization from acetone-hexane gave a red solid having m.p. 128°-130°, [α]D 22 +44° (c 0.03, chloroform); 1 H-n.m.r. (200 MHz, CDCl3): 13.59, 13.31 (s, 1H, HO-6,11), 8.37, 7.85 (m, 2H, H-1,2,3,4), 5.75 (s, 1H, H-1'), 5.26 (dd, 1H, H-7), 5.19 (t, 1H, J4',5' 9.8 Hz, H-4'), 4.63 (dd, 1H, J1',2' 1.4 Hz, H-2'), 4.36 (dd, 1H, J2',3' 4.4, J3',4' 9.3 Hz, H-3'), 4.10 (qd, 1H, H-5'), 4.08 (s, 1H, HO-9), 3.31 (dd, 1H, J8e,10e 1.0 Hz, H-10e), 3.07 (d, 1H, J10a,10e 18.9 Hz, H-10a), 2.36 (bd, 1H, H-8e), 2.22 (dd, 1H, J7,8a 4.2, J8a,8e 15.5 Hz, H-8a), 2.07, 2.05 (s, 3H, OAc), 1.29 (d, 3H, J5',6' 6.3 Hz, H-6'), 0.96 (s, 9H, CMe3), and 0.15 (s, 6H, Me2 Si).

Anal. Calc. for C36 H43 IO13 Si: C, 51.55; H, 5.17; I, 15.13. Found: C, 51.44; H, 5.18; I, 15.02.

SYNTHESIS EXAMPLE 3 (7S,9S)-14-O-(tert-butyldimethylsilyl)-4-demethoxy-7-O-(2,6-dideoxy-2-iodo-α-L-manno-hexopyranosyl)adriamycinone (5)

Compound (3) (197 mg, 0.23 mmol) was dissolved in methanol (12 ml) and then methanolic sodium methoxide (1.7 ml of 0.45 mmol/ml) was added. The reaction was subsequently terminated by making the solution neutral with solid carbon dioxide, whereupon thin layer chromatography (4:1 toluene-acetone) showed (3) to be absent. The solution was poured into water and the product extracted with dichloromethane. The organic phase was washed twice with water, dried with magnesium sulfate, and evaporated under diminished pressure. Crystallization from acetone-hexane gave 90.5 mg (51%) of compound (5) as red crystals having m.p. 179°-181°, [α]D 22 +15° (c 0.03, chloroform); 1 H-n.m.r. (200 MHz, CDCl3): 13.61, 13.28 (s, 1H, HO-6,11), 8.35, 7.85 (m, 2H, H-1,2,3,4), 5.77 (s, 1H, H-1'), 5.24 (dd, 1H, J7,8e 1.9 Hz, H-7), 4.88 (AB pattern, 2H, H-14), 4.54 (dd, 1H, J1',2' 1.0 Hz, H-2'), 4.12 (s, 1H, HO-9), 3.94 (dq, 1H, J4',5' 9.3, J5',6' 6.3 Hz, H-5'), 3.58 (td, 1H, J3',4' 9.1, J4',HO-4' 3.2 Hz, H-4'), 3.27 (dd, 1H, J8e,10e 1.3 Hz, H-10e), 3.04 (d, 1H, J10a,10e 19.0 Hz, H-10a), 2.85 (ddd, 1H, J2',3' 4.1, J3',HO-3' 7.6 Hz, H-3'), 2.38 (bd, 1H, J8a,8e 15.0 Hz, H-8e), 2.32 (d, 1H, HO-4'), 2.21 (dd, 1H, J7,8a 4.2 Hz, H-8a), 1.39 (d, 3H, H-6') 0.95 (s, 9H, CMe3), 0.14 (s, 6H, Me2 Si); signals of HO-3',4',6,9 and -11 disappeared when a drop of D2 O was added; 13 C-n.m.r. (50 MHz, CDCl3): 210.8 (C═O), 186.8, 186.6 (C-5,12), 156.4, 156.2 (C-6,11), 135.7, 134.7, 133.4, 133.3, 132.6, 127.2, 127.0 (C-1,2,3,4,4a,6a,10a,12a), 111.7, 111.0 (C-5a,11a) 104.8 (C-1'), 76.9 (C-9), 75.5 (C-4'), 70.5 (C-5',7), 69.3 (C-3'), 66.6 (C-14), 36.9 (C-2'), 35.6 (C-8), 34.0 (C-10), 25.9 (CMe3), 18.5 (CMe3), 17.6 (C-6'), -5.3, -5.4 (Me2 Si).

Anal. Calc. for C32 H39 IO11 Si: C, 50.93; H, 5.21; I, 16.82. Found: C, 50.76; H, 5.26; I, 16.91.

SYNTHESIS EXAMPLE 4 (7S,9S)-4-Demethoxy-7-O-(2,6-dideoxy-2-iodo-α-L-manno-hexopyranosyl)adriamycinone (6)

Compound (5) (90.0 mg, 0.12 mmol) was dissolved in a mixture of dichloromethane (1 ml) and oxolane (5 ml), and then pyridine (50 μl) and 180 μl of a 1M solution of tetrabutylammonium fluoride in oxolane was added. The reaction was terminated after 40 min by dilution with dichloromethane and washing with water. The organic phase was dried with magnesium sulfate and evaporated under diminished pressure. Crystallization from dichloromethane-acetone-hexane gave 31 mg (41%) of a red solid, m.p. 173°-175° (dec.); 1 H-n.m.r. (200 MHz, acetone-d6): 8.38, 8.01 (m, 2H, H-1,2,3,4), 5.73 (s, 1H, H-1'), 5.26 (dd, 1H, J7,8a 5.0, J7,8e 3.0 Hz, H-7), 4.52 (dd, J1',2' 1.0, J2',3' 4.0 Hz, H-2').

As demonstrated by the following biological examples, the compounds of the present invention display significant anticancer activity in animals with less toxicity than 4-demethoxydoxorubicin. Among other effects, the compounds of the present invention show antileukemic activity against murine P388 leukemia and B-16 melanoma. Furthermore, when administered in their optimum dosage, the compounds of the present invention are accompanied by less incidence of lesions.

BIOLOGICAL EXAMPLE 1

Groups of mice were inoculated by intraperitoneal injection with the lymphocytic leukemia cell line P-388 or the solid tumor cell line B-16 melanoma. On day 1, 24 hours after implantation of the tumor cells, groups of test mice were administered a single intraperitoneal dose of the compound 4-demethoxy-7-O-(2-iodo-2,6-dideoxy-α-L-manno-hexapyranosyl)adriamycinone. For comparative purposes, similar groups of mice challenged with the P-388 or B-16 tumor cells were given a single dose of doxorubicin hydrochloride on day 1 following implantation of the tumor cells. The animals were observed and their survival compared with that of control animals which received the same tumor inoculation but were not treated with the drug. The T/C, a ratio of the test Median Survival Time (MST) relative to control MST was determined. An increase in the T/C indicates an increase in the antitumor activity of the compound. If T/C is less than 100, the compound is considered toxic. Testing in the P-388 line showed that compound 6 administered at a dosage of 3.12 mg/kg demonstrated a T/C of 218. A doxorubicin hydrochloride dosage of 5 mg/kg showed a T/C of 180. Compound 6 also demonstrated activity in the more resistant B-16 solid tumor. Dosages of 5 and 2.5 mg/kg were active with T/C of 184 and 177 respectively. A 20 mg/kg doxorubicin hydrochloride dosage elicited a T/C of 104.

BIOLOGICAL EXAMPLE 2

Additional studies were performed to examine the extravasation potential of 4-demethoxy-7-O-(2-iodo-2,6-dideoxy-α-L-manno-hexapyranosyl)adriamycinone. Groups of mice (10/group) were injected subcutaneously with 0.2 ml or 0.1 ml of the test compound suspended in cremophor at a concentration of 1.0 mg/ml. Similar groups were given 0.2 ml or 0.1 ml of doxorubicin hydrochloride suspended in cremophor at a concentration of 2.0 mg/ml. Control groups received 0.2 ml of cremophor. The animals were observed frequently for lesions. The test showed that the number of animals with demonstrable lesions in the groups administered the test compound were substantially lower in comparison to those noted in groups administered doxorubicin hydrochloride. The results are reported in the Table below.

              TABLE______________________________________           Number of animals with lesions      Dosage Day 5       Day 9______________________________________Compound 6   0.1 mg   1/10        1/10Doxorubicin  0.2 mg   6/10        10/10Compound 6   0.2 mg   1/10        3/10Doxorubicin  0.4 mg   8/10        10/10Cremophor (control)        0.2 mg   0/10        0/10______________________________________

Having described the invention in detail and by reference to specific embodiments thereof, it will be apparent that numerous variations are possible without departing from the spirit and scope of the invention defined by the following claims.

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4675311 *Oct 16, 1985Jun 23, 1987Farmitalia Carlo Erba, S.P.A.Pharmaceutical compositions containing anthracycline glycosides
US4863739 *May 19, 1987Sep 5, 1989Board Of Regents, The University Of Texas SystemLiposome compositions of anthracycline derivatives
US4870058 *Feb 3, 1988Sep 26, 1989Ohio State University Research Foundation14-Acyloxy-2'-halo-anthracycline anti-cancer antibiotics
US4973674 *Apr 11, 1988Nov 27, 1990Farmitalia Carlo Erba S.R.L.Chiral synthesis of anthracyclines from substituted anthraquinones
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US5132290 *May 30, 1989Jul 21, 1992The Board Of Regents, The University Of Texas SystemEsters of 3'-deaminodoxorubicin and liposomal compositions thereof
US5625043 *Feb 27, 1995Apr 29, 1997Waldemar PriebeAnthracyclines with unusually high activity against cells resistant to doxorubicin and its analogs
US5902604 *Jun 6, 1995May 11, 1999Board Of Regents, The University Of Texas SystemSubmicron liposome suspensions obtained from preliposome lyophilizates
US5945518 *Mar 19, 1996Aug 31, 1999Sicor Societa' Italiana Corticosteroida S.p.A.Process for the preparation of anthracycline antibiotics
US5977327 *Jul 22, 1997Nov 2, 1999Board Of Regents, The University Of Texas SystemSynthesis of annamycin
US7238366Jul 24, 1998Jul 3, 2007Board Of Regents, The University Of Texas SystemSubmicron liposome suspensions obtained from preliposome lyophilizates
EP1634887A2Jun 30, 2005Mar 15, 2006Zaklad Badawczo-ProdukcyjnyProcess for synthesis of complex 2-deoxy-2-iodo pyranosides of high purity, particularly suitable for manufacturing pharmaceutically pure annamycin
WO1988009166A1 *May 18, 1988Dec 1, 1988Board Of Regents, The University Of Texas SystemLiposome compositions of anthracycline derivatives
WO1990000173A1 *Jun 9, 1989Jan 11, 1990Board Of Regents, The University Of Texas System4'-deoxy-2'-halo-anthracycline antibiotics, methods for their use, and intermediates and methods for synthesis thereof
WO1990007519A1 *Oct 23, 1989Jul 12, 1990Board Of Regents, The University Of Texas System3'-deamino analogs of esorubicin and methods for their use
WO1998003522A1 *Jul 23, 1997Jan 29, 1998Board Of Regents, The University Of Texas SystemImprovements in the synthesis of annamycin
WO2007003236A1 *Mar 14, 2006Jan 11, 2007Zaclad Badawczo-Produkcyjny 'syntex'Process for synthesis of complex 2-deoxy-2-iodo pyranosides of high purity, particularly suitable for manufacturing pharmaceutically pure annamycin
Classifications
U.S. Classification514/34, 536/6.4, 552/201
International ClassificationC07H15/252
Cooperative ClassificationC07H15/252
European ClassificationC07H15/252
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